The D vitamins are very important agents for the control of calcium and phosphate metabolism in animals and humans, and have long been used as dietary supplements and in clinical practice to assure proper bone growth and development. It is now known that the in vivo activity of these vitamins, specifically of vitamin D.sub.2 and D.sub.3, is dependent on metabolism to hydroxylated forms. Thus, vitamin D.sub.3 undergoes two successive hydroxylation reactions in vivo, leading first to 25-hydroxyvitamin D.sub.3 and then to 1,25-dihydroxyvitamin D.sub.3 and the latter is thought to
be the compound responsible for the well-known beneficial effects of vitamin D.sub.3. Likewise, vitamin D.sub.2, which is commonly used as a dietary supplement, undergoes an analogous hydroxylation sequence to its active forms, being first converted to 25-hydroxyvitamin D.sub.2 (25-OH-D.sub.2) and then to 1,25-dihydroxyvitamin D.sub.2 (1,25-(OH).sub.2 D.sub.2). These facts are well established and well known in the art [see, for example, Suda et al. Biochemistry 8, 3515 (1969) and Jones et al. Biochemistry 14, 1250 (1975)].
Like the metabolites of the vitamin D.sub.3 series, the hydroxylated forms of vitamin D.sub.2 named above are, because of their potency and other beneficial properties, highly desirable dietary supplements, or pharmaceutical agents, for the cure or prevention of bone or related diseases, and their value and possible use is recognized in patents relating to these compounds [U.S. Pat. Nos. 3,585,221 and 3,880,894].
Whereas many metabolites of vitamin D.sub.3 have been prepared by chemical synthesis, there has been less work on the preparation of vitamin D.sub.2 metabolites. The known synthetic processes for the metabolites of the D.sub.3 -series (especially as far as they relate to the preparation of side chain hydroxylated compounds) are, of course, in general not suitable for the preparation of the corresponding vitamin D.sub.2 metabolites, since the latter are characterized by a side chain structure (i.e. presence of a double bond and an extra methyl group) which requires a different synthetic approach from that applicable to side chain hydroxylated D.sub.3 compounds.
Various approaches for the preparation of vitamin D.sub.2 metabolites are known, and are described in U.S. Pat. Nos. 4,448,721, 4,847,012 and 4,769,181. Other preparations of 25-OH-D.sub.2 and 1.alpha.,25-(OH).sub.2 D.sub.2 compounds involving condensation of side chains with a steroid nucleus are shown in Yamada et al, "Facile And Stereoselective Synthesis of 25-hydroxyvitamin D.sub.2 ", Tetrahedron Letters, Vol. 25, No. 33, pp. 3347-3350, 1984 and in Tsuji et al, "A New And Convenient Synthesis of 1.alpha.,25-Dihydroxyvitamin D.sub.2 And Its 24R-Epimer", Bull, Chem. Soc. Jpn., Vol. 62, No. 10, pp. 3132-3137, 1989. Perlman et al have reported the preparation of the epimer of 1.alpha.-OH-D.sub.2 by condensation of a suitable side chain fragment with a vitamin D nucleus in J. Chem. Soc. Chem. Com. pp. 1113-1115, 1989.
The natural vitamin D-derived hormone, 1.alpha.,25-dihydroxyvitamin D.sub.3, and its 25-deoxy analog, 1.alpha.-hydroxyvitamin D.sub.3, both exhibit high activity in vivo, being known as potent stimulators of the intestinal absorption of calcium and the mobilization of calcium from bone and as effective promoters of bone calcification. A very similar activity pattern is shown by 1.alpha.,25-dihydroxyvitamin D.sub.2 (U.S. Pat. No. 3,880,894) and its 25-deoxy analog, 1.alpha.-hydroxyvitamin D.sub.2 (U.S. Pat. No. 3,907,843) . These compounds likewise elicit the full spectrum of vitamin D-type responses such as intestinal calcium transport, bone mineral mobilization and bone calcification response in the animal or human. Structurally, 1.alpha.,25-dihydroxyvitamin D.sub.2 and 1.alpha.-hydroxyvitamin D.sub.2 are characterized by having a C-24 stereochemistry as it occurs in the side chain of ergosterol, i.e. these compounds are defined by the structures shown below, where R represents side chains (a) and (b), respectively: ##STR1## More recently the C-24-epimer of 1.alpha.,25-dihydroxyvitamin D.sub.2 and 1.alpha.-hydroxyvitamin D.sub.2 has been prepared and tested. These compounds are characterized by the structures shown above, where R represents side chains (c) and (d) respectively. Remarkably these C-24-epimeric vitamin D derivatives exhibit a distinctly different biological activity in that they promote intestinal calcium absorption and the calcification of bone, but elicit little or no bone calcium mobilization response.